Multiple drug resistance (MDR) is a well-known phenomenon wherein target cells, for example cancer cells, become resistant during treatment to different, structurally unrelated drugs in addition to the drug being used (Nooter et al., Br. J. Cancer, 63:663-669 (1991), incorporated herein by reference). Some compounds, such as verapamil, diltiazem, cyclosporin and catharanthine, are known to attenuate, if not reverse, drug resistance in certain mammalian target cells. While not intending to be limited by theory, it is believed that compounds affecting MDR interact with a membrane glycoprotein (P-170), a member of a superfamily of membrane transport proteins, which is the main component of membrane-associated drug efflux systems and is overexpressed in MDR cells. MDR resistance in other organisms, as for example resistance to the antimalarial drug chloroquine in Plasmodium falciparum and antimony resistance in Leishmania species, occurs by very similar mechanisms. Thus MDR-attenuating compounds have potential as adjuncts in antimalarial and other antiprotozoal as well as anticancer therapy.
Unfortunately, not all cells that develop MDR are responsive to known MDR attenuators. Moreover, some known MDR attenuators are active in vivo only at or near the toxic dose of these agents. There is therefore a continuing need for new compounds with MDR-attenuating activity.
The compounds of the present invention are related to but distinct from asperlicins, which are isolated from Aspergillus alliaceus and have activity as cholecystokinin antagonists (Leisch et al., J. Antibiotics, 38:1638-1641 (1985); Goetz et al., J. Antibiotics, 38:1631-1637 (1985); Houck et al., U.S. Pat. No. 4,696,925 (1987); Leish et al., J. Antibiotics, 41:878-881 (1988)).